Mice Deficient in the Insulin-regulated Membrane Aminopeptidase Show Substantial Decreases in Glucose Transporter GLUT4 Levels but Maintain Normal Glucose Homeostasis

Keller, Susanna R.; Davis, A C; Clairmont, Kevin B.

doi:10.1074/jbc.m202037200

Cited by 111 publications

(111 citation statements)

References 69 publications

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“…We furthermore provide correlative evidence (r 2 ϭ 0.47, P ϭ 0.05) that training-induced changes in GLUT4 protein occur in coordination with changes in protein expression of IRAP. This finding is supported by a previous cross-sectional human study (55) and suggests that also in human muscle IRAP is not only a marker of GLUT4-containing vesicles but also may be directly involved in maintaining GLUT4 expression and vesicle trafficking (28,56). In the present study, an ϳ200% increase in the protein content of HK2 was observed.…”

supporting

confidence: 80%

Effects of Endurance Exercise Training on Insulin Signaling in Human Skeletal Muscle

et al. 2007

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The purpose of this study was to investigate the mechanisms explaining improved insulin-stimulated glucose uptake after exercise training in human skeletal muscle. Eight healthy men performed 3 weeks of one-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was ϳ60% higher (P < 0.01) in the trained compared with the untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies were obtained before and after training as well as after 10 and 120 min of insulin stimulation in both legs. Protein content of Akt1/2 (55 ؎ 17%, P < 0.05), AS160 (25 ؎ 8%, P ‫؍‬ 0.08), GLUT4 (52 ؎ 19%, P < 0.001), hexokinase 2 (HK2) (197 ؎ 40%, P < 0.001), and insulin-responsive aminopeptidase (65 ؎ 15%, P < 0.001) increased in muscle in response to training. During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P < 0.005), and glycogen synthase (GS) (percent I-form, P < 0.05) increased similarly in both trained and untrained muscle, consistent with increased phosphorylation of Akt Thr 308 , Akt Ser 473 , AS160, glycogen synthase kinase (GSK)-3␣ Ser 21 , and GSK-3␤ Ser 9 and decreased phosphorylation of GS site 3a؉b (all P < 0.005). Interestingly, training improved insulin action on thigh blood flow, and, furthermore, in both basal and insulin-stimulated muscle tissue, activities of Akt1 and GS and phosphorylation of AS160 increased with training (all P < 0.05). In contrast, training reduced IRS-1-associated PI3-K activity (P < 0.05) in both basal and insulin-stimulated muscle tissue. Our findings do not support generally improved insulin signaling after endurance training; rather it seems that improved insulin-stimulated glucose uptake may result from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism.

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confidence: 80%

Effects of Endurance Exercise Training on Insulin Signaling in Human Skeletal Muscle

et al. 2007

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“…Interestingly, Glut4 Ϫ/Ϫ mice (similar to our Tnks2 PARP-deleted mice) display growth retardation and are 20% smaller than controls (31). However, since IRAP Ϫ/Ϫ mice do not have decreased body weight (33), the role of the IRAP-tankyrase 2 interaction in the small mouse phenotype remains to be determined.…”

Section: Discussionmentioning

confidence: 97%

“…After insulin stimulation, both IRAP and GLUT4 translocate from vesicles in the cytoplasm and trans-Golgi network to the plasma membrane (reviewed in reference 32). In IRAP Ϫ/Ϫ mice, absence of IRAP resulted in decreased GLUT4 expression (33). It has been suggested that tankyrases 1 and 2 may have a role in targeting or maintenance of GLUT4 vesicles (11,50).…”

Section: Discussionmentioning

confidence: 99%

Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

Hsiao

Poitras

Cook

et al. 2006

Molecular and Cellular Biology

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Regulation of telomere length maintenance and capping are a critical cell functions in both normal and tumor cells. Tankyrase 2 (Tnks2) is a poly(ADP-ribose) polymerase (PARP) that has been shown to modify itself and TRF1, a telomere-binding protein. We show here by overexpression studies that tankyrase 2, like its closely related homolog tankyrase 1, can function as a positive regulator of telomere length in human cells, dependent on its catalytic PARP activity. To study the role of Tnks2 in vivo, we generated mice with the Tnks2 PARP domain deleted. These mice are viable and fertile but display a growth retardation phenotype. Telomere analysis by quantitative fluorescence in situ hybridization (FISH), flow-FISH, and restriction fragment analysis showed no change in telomere length or telomere capping in these mice. To determine the requirement for Tnks2 in long-term maintenance of telomeres, we generated embryonic stem cells with the Tnks2 PARP domain deleted and observed no change, even upon prolonged growth, in telomere length or telomere capping. Together, these results suggest that Tnks2 has a role in normal growth and development but is not essential for telomere length maintenance or telomere capping in mice.

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“…IRAP null mice exhibit apparently normal GLUT4 translocation (Keller et al, 2002), indicating, as expected, that the cytoplasmic domains of GLUT4 possess the information requisite for proper GSV trafficking. Indeed and as noted above, dileucine and acidic cluster sequences in IRAP's N-terminus are very similar to those in the GLUT4 C-terminus.…”

Section: Molecular Biology Of the Cell 2888mentioning

confidence: 91%

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

Hosaka

Brooks

Presman

et al. 2005

MBoC

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Insulin-regulated aminopeptidase (IRAP) is an abundant cargo protein of Glut4 storage vesicles (GSVs) that traffics to and from the plasma membrane in response to insulin. We used the amino terminus cytoplasmic domain of IRAP, residues 1-109, as an affinity reagent to identify cytosolic proteins that might be involved in GSV trafficking. In this way, we identified p115, a peripheral membrane protein known to be involved in membrane trafficking. In murine adipocytes, we determined that p115 was localized to the perinuclear region by immunofluorescence and throughout the cell by fractionation. By immunofluorescence, p115 partially colocalizes with GLUT4 and IRAP in the perinuclear region of cultured fat cells. The amino terminus of p115 binds to IRAP and overexpression of a N-terminal construct results in its colocalization with GLUT4 throughout the cell. Insulin-stimulated GLUT4 translocation is completely inhibited under these conditions. Overexpression of p115 C-terminus has no significant effect on GLUT4 distribution and translocation. Finally, expression of the p115 N-terminus construct has no effect on the distribution and trafficking of GLUT1. These data suggest that p115 has an important and specific role in insulin-stimulated Glut4 translocation, probably by way of tethering insulin-sensitive Glut4 vesicles at an as yet unknown intracellular site. INTRODUCTIONInsulin normalizes blood glucose levels by mobilizing the muscle and adipocyte glucose transporter isoform, GLUT4, from intracellular storage vesicles and moving it to the plasma membrane (Simpson et al., 2001;Bryant et al., 2002). Various models of GLUT4 trafficking suggest that GLUT4 must exist in more than one intracellular compartment and the major insulin sensitive pool is localized to a compartment that is distinct from endosomal markers and is commonly referred to as glucose transporter storage vesicles (GSVs), or insulin responsive vesicle (IRVs). Despite the critical function of glucose transport in glucose homeostasis, many of the details by which adipocytes and muscle form a pathway of insulin-sensitive GLUT4 trafficking remain unknown. However, it is virtually certain that the major cargo proteins of GSVs must interact with a number of cytosolic and membrane proteins, such as adaptors and tethers, in order to be properly sorted and regulated by insulin.Insulin-responsive aminopeptidase (IRAP) was identified as an abundant cargo protein associated with GLUT4 vesicles that translocates in response to insulin in a manner seemingly identical to GLUT4 Mastick et al., 1994;Keller et al., 1995;Malide et al., 1997;Martin et al., 1997;Ross et al., 1997). In fact, it is more abundantly expressed in vesicles than the transporter (Kupriyanova et al., 2002). When the cytoplasmic N-terminus of IRAP was microinjected into 3T3-L1 adipocytes, GLUT4 was localized on the plasma membrane even in the basal state (Waters et al., 1997), suggesting IRAP can play a role in GSV movement/targeting. A chimeric protein containing the intracellular domain of IRAP and ...

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Mice Deficient in the Insulin-regulated Membrane Aminopeptidase Show Substantial Decreases in Glucose Transporter GLUT4 Levels but Maintain Normal Glucose Homeostasis

Cited by 111 publications

References 69 publications

Effects of Endurance Exercise Training on Insulin Signaling in Human Skeletal Muscle

Effects of Endurance Exercise Training on Insulin Signaling in Human Skeletal Muscle

Tankyrase 2 Poly(ADP-Ribose) Polymerase Domain-Deleted Mice Exhibit Growth Defects but Have Normal Telomere Length and Capping

p115 Interacts with the GLUT4 Vesicle Protein, IRAP, and Plays a Critical Role in Insulin-stimulated GLUT4 Translocation

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